The movement disorder spectrum of SCA21 (ATX-TMEM240): 3 novel families and systematic review of the literature

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Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) was recently found to be caused by mutations in TMEM240, with still limited knowledge on the phenotypic spectrum and disease course. Here we present five subjects from three novel SCA21 families from different parts of the world (including a novel c.196G>A, p.G66R TMEM240 variant from Colombia), demonstrating that, in addition to cerebellar ataxia, not only hypokinetic features (hypomimia, bradykinesia), but also hyperkinetic movement disorders (poly-mini-myoclonus, proximal myoclonus) are a recurrent part of the phenotypic spectrum of SCA21. Presenting first prospective longitudinal data, our results provide examples of two different disease trajectories: while it was inherently progressive in adult-onset cases, a dramatically improving trajectory was observed in an infantile-onset case. A systematic review of all previously reported SCA21 patients (n=42) demonstrates that SCA21 is a relatively early-onset SCA (median onset age 18 years; range 1-61 years) with frequent non-cerebellar involvement, including hyporeflexia (69%), bradykinesia (65%), slow saccades (38%) and pyramidal signs (17%). Our results characterize SCA21 as a multisystem disorder with substantial extra-cerebellar involvement, including a wide spectrum of hypo- as well as hyperkinetic movement disorders as well as damage to the midbrain, corticospinal tract and peripheral nerves. However, in contrast to the current perspective on SCA21 disease, cognitive impairment is not an obligatory feature of the disease. The disease course is inherently progressive in adult-onset subjects, but might also be characterized by improvement in infantile-onset cases. These findings have important consequences of the work-up and counseling of SCA21/ATX-TMEM240 patients.